Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study

Abstract

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. FUNDING: British Heart Foundation, UK Medical Research Council, and Academy of Finland.

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References 33

1. 1.

   Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89.

   Not in our library10.1016/s2213-8587(13)70165-7

2. 2.

   Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2:307-20.

   Not in our library10.1016/s2213-8587(13)70212-2

3. 3.

   Tamez H, Thadhani RI. Vitamin D and hypertension: an update and review. Curr Opin Nephrol Hypertens. 2012;21:492-99.

   Not in our library10.1097/mnh.0b013e3283557bf0

4. 4.

   Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women’s Health Initiative randomized trial. Hypertension. 2008;52:847-55.

   Not in our library10.1161/hypertensionaha.108.114991

5. 5.

   Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009;27:1948-54.

   Not in our library10.1097/hjh.0b013e32832f075b

6. 6.

   Forman JP, Scott JB, Ng K, et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 2013;61:779-85.

   Not in our library10.1161/hypertensionaha.111.00659

7. 7.

   Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:1931-42.

   Not in our library10.1210/jc.2011-0398

8. 8.

   Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32:1-22.

   Not in our library10.1093/ije/dyg070

9. 9.

   Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376:180-88.

   Not in our library10.1016/s0140-6736(10)60588-0

10. 10.

    Berry DJ, Vimaleswaran KS, Whittaker JC, Hingorani AD, Hyppönen E. Evaluation of genetic markers as instruments for mendelian randomization studies on vitamin D. PLoS One. 2012;7:e37465.

    Not in our library10.1371/journal.pone.0037465

11. 11.
    Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts · 2013

    No notice
12. 12.

    Chun RF, Lauridsen AL, Suon L, et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010;95:3368-76.

    Not in our library10.1210/jc.2010-0195

13. 13.

    Jones G, Prosser DE, Kaufmann M. 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012;523:9-18.

    Not in our library10.1016/j.abb.2011.11.003

14. 14.

    Ehret GB, Munroe PB, Rice KM, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103-09.

    Not in our library10.1038/nature10405

15. 15.

    Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666-76.

    Not in our library10.1038/ng.361

16. 16.

    Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677-87.

    Not in our library10.1038/ng.384

17. 17.

    Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev. 1998;78:1193-231.

    Not in our library10.1152/physrev.1998.78.4.1193

18. 18.

    Rice JA. Mathematical statistics and data analysis. 1995.

    Not in our library

19. 19.
    Using multiple genetic variants as instrumental variables for modifiable risk factors · 2011

    No notice
20. 20.

    Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27:1133-63.

    Not in our library10.1002/sim.3034

21. 21.

    Thomas DC, Lawlor DA, Thompson JR. Re: Estimation of bias in nongenetic observational studies using “Mendelian triangulation” by Bautista et al. Ann Epidemiol. 2007;17:511-13.

    Not in our library10.1016/j.annepidem.2006.12.005

22. 22.

    Kunutsor SK, Burgess S, Munroe PB, Khan H. Vitamin D and high blood pressure: causal association or epiphenomenon? Eur J Epidemiol. 2014;29:1-14.

    Not in our library10.1007/s10654-013-9874-z

23. 23.

    Pittas AG, Chung M, Trikalinos T, et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307-14.

    Not in our library10.1059/0003-4819-152-5-201003020-00009

24. 24.

    Witham MD, Price RJ, Struthers AD, et al. Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med. 2013;173:1672-79.

    Not in our library10.1001/jamainternmed.2013.9043

25. 25.

    Kupferschmidt K. Uncertain verdict as vitamin D goes on trial. Science. 2012;337:1476-78.

    Not in our library10.1126/science.337.6101.1476

26. 26.

    Freundlich M, Quiroz Y, Zhang Z, et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int. 2008;74:1394-402.

    Not in our library10.1038/ki.2008.408

27. 27.

    Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110:229-38.

    Not in our library10.1172/jci15219

28. 28.

    Schroten NF, Ruifrok WP, Kleijn L, et al. Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial). Am Heart J. 2013;166:357-64.

    Not in our library10.1016/j.ahj.2013.05.009

29. 29.

    Tiosano D, Schwartz Y, Braver Y, et al. The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR). J Bone Miner Res. 2011;26:2252-60.

    Not in our library10.1002/jbmr.431

30. 30.

    Mehrotra R, Kermah DA, Salusky IB, et al. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Kidney Int. 2009;76:977-83.

    Not in our library10.1038/ki.2009.288

31. 31.

    Mutt SJ, Karhu T, Lehtonen S, et al. Inhibition of cytokine secretion from adipocytes by 1,25-dihydroxyvitamin D(3) via the NF-κB pathway. FASEB J. 2012;26:4400-07.

    Not in our library10.1096/fj.12-210880

32. 32.

    Schooling CM, Au Yeung SL, Freeman G. Mendelian randomization estimates may be inflated. J Am Coll Cardiol. 2013;61:1931.

    Not in our library10.1016/j.jacc.2012.12.049

33. 33.

    Skaaby T, Husemoen LL, Martinussen T, et al. Vitamin D status, filaggrin genotype, and cardiovascular risk factors: a Mendelian randomization approach. PLoS One. 2013;8:e57647.

    Not in our library10.1371/journal.pone.0057647

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• Association of 25-hydroxyvitamin D with cardiometabolic risk factors and metabolic syndrome: a mendelian randomization study · 2019
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• Vitamin D deficiency and risk of cardiovascular diseases: a narrative review · 2018
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• Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data · 2017
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• Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study · 2015
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• Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study · 2015
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